PROJECT SUMMARY/ABSTRACT The objective of this proposal is to train David R. Raleigh, MD, PhD, a candidate with an excellent foundation for basic science research, to become an independent investigator of brain tumor biology. The proposed research also aims to improve treatments for patients with medulloblastoma, a common pediatric brain cancer. The proposed research addresses limitations that have hindered therapeutic advancements for patients with medulloblastoma by identifying novel, druggable targets that transduce oncogenic Hedgehog signaling via the primary cilium. The candidate's central hypothesis is that the oxysterol synthase Hsd11β2 generates ciliary oxysterols that activate Hedgehog signaling and induce Cdk6 to drive uncontrolled cell proliferation. This work will elucidate (1) how oncogenic Hh signaling is transduced to cause cell growth; and (2) whether blocking this signaling is an effective therapeutic strategy for Hh-associated medulloblastoma. Toward those goals, the following specific aims are proposed: (1) determine how Hsd11β2 contributes to ciliary Hedgehog signaling; and (2) define how Hedgehog signaling misactivates Cdk6 in medulloblastoma. The candidate's training and research plan incorporates a combination of coursework, workshops, mentoring, and hand-on research experience set in the outstanding academic environment of UCSF, a center of excellence in medicine and research endowed with a well-integrated community of clinicians and scientists. The candidate's mentor is Dr. Jeremy Reiter, a recognized expert and pioneer in mouse genetic models and the molecular mechanisms of vertebrate Hedgehog signaling through the primary cilium., both in development and in cancer. The candidate's multidisciplinary advisory committee includes distinguished scientists with expertise in all areas covered by the research strategy of this award. Successful completion of the proposed research will produce compelling preclinical rationale for testing specific targeted inhibitors in patients within biomarker-defined subsets of Hedgehog-associated medulloblastoma. The intermediate-term goal is for the candidate to acquire the knowledge, technical skill and expertise necessary to submit a successful R01 proposal. Long-term goals are for the integrated, preclinical platform of Hedgehog-associated medulloblastoma developed in this proposal to inform treatment decisions and improve survival of medulloblastoma patients.